Identification of distant co-evolving residues in antigen 85C from Mycobacterium tuberculosis using statistical coupling analysis of the esterase family proteins

Veeky Baths,Utpal Roy

doi:10.1016/s1674-8301(11)60021-3

Abstract

A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originating at one site in a protein propagate reliably to affect distant functional sites. The general principles of protein structure that underlie this process remain unknown. Statistical coupling analysis (SCA) is a statistical technique that uses evolutionary data of a protein family to measure correlation between distant functional sites and suggests allosteric communication. In proteins, very distant and small interactions between collections of amino acids provide the communication which can be important for signaling process. In this paper, we present the SCA of protein alignment of the esterase family (pfam ID: PF00756) containing the sequence of antigen 85C secreted by Mycobacterium tuberculosis to identify a subset of interacting residues. Clustering analysis of the pairwise correlation highlighted seven important residue positions in the esterase family alignments. These residues were then mapped on the crystal structure of antigen 85C (PDB ID: 1DQZ). The mapping revealed correlation between 3 distant residues (Asp38, Leu123 and Met125) and suggests allosteric communication between them. This information can be used for a new drug against this fatal disease.

Highlights

Communication between distant sites in proteins is fundamental to their function and often defines the biological role of a protein family
The conservation of an amino acid a at position i in a multiple sequence alignment is defined by the divergence of the observed frequency of a at I (fi(a)) from the background frequency of a in all proteins (q(a))[8]
For all but the least conserved positions, the overall conservation of all amino acids at each position i is well approximated by Di(ai), the conservation of ai, the most prevalent amino acid at that position[13]

Summary

Introduction

Communication between distant sites in proteins is fundamental to their function and often defines the biological role of a protein family. In signaling proteins, it represents information transfer -- the transmission of signals initiated at one functional surface to a distinct surface mediating downstream signaling. Ligand binding at an externally accessible site in G protein-coupled receptors (GPCRs) reliably triggers structural changes at distant cytoplasmic domains that mediate interaction with heterotrimeric G proteins[1,2]. Statistical coupling analysis (SCA) is a technique used to identify communication between distant sites in proteins.

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